The Ligand Substitution Reactions of Hydrophobic Vitamin B12 Derivatives. Reaction of Cobyric Acid Heptapropyl Ester with Heterocyclic N-donor Ligands

The hydrophobic cobyrinic acid heptapropyl ester corrinoids XCbs-Pr (axial ligand X=CN–, SO32–, CH3– and CH3CH2–) have been prepared from vitamin B12 by hydrolysis of the amide side chains and their conversion to propyl esters. Both the position of the γ-band and the general shape of the UV-visible spectra of these complexes show significant solvent dependence as the polarity of the solvent is varied. The equilibrium constants, K, for the reaction of five-membered heterocyclic nitrogenous bases (the azoles imidazole, pyrazole and 1,2,4-triazole) with displacement of coordinated H2O in aquacyanocobyrinic acid heptapropyl ester, and coordination by the predominantly five-coordinate complexes sulphitocobyrinic acid heptapropyl ester, ethylcobyrinic acid heptapropyl ester and methylcobyrinic acid heptapropyl ester, have been determined spectrophotometrically at 25 °C in water, methanol, acetonitrile, ethyl acetate and toluene. Values of K are dependent on the identity of the trans ligand (X=CN–>SO3 2–> CH3 – > CH3CH2 –); they increase with the basicity of the azole (pyrazole < 1,2,4-triazole < imidazole); and they increase as the solvent polarity increases (toluene<ethyl acetate< acetonitrile< methanol< H2O). Molecular mechanics calculations suggest that these effects are largely electronic in origin.Keywords: Hydrophobic vitamin B12, cobalt corrinoids, equilibrium constants, solvent polarity, trans influencePDF and Supplementry file attache

The Kinetics of the Silver(i)-induced Oxidation of Chromium(iii) by Peroxodisulphate

Chromium(III) and chromium(VI) compounds play an important role in natural oxidation processes in terrestrial and atmospheric water. During the oxidation of SO2, peroxodisulphate is formed as an intermediate. In acidic and neutral solutions, peroxodisulphate oxidizes chromium(III) very slowly. This reaction rate is markedly enhanced by silver ions, resulting in a reaction rate that allows the reaction to be studied conveniently under laboratory conditions. The kinetics of the Cr(III)/Ag(I)/S2O82– reaction system were studied as a function of different Cr(III), Ag(I) and S2O82– concentrations, temperature and pressure. The formation of Cr(VI) was observed as a first-order process at high [Cr(III)] and as a zero-order process at low [Cr(III)].Aninduction period was observed in both cases. For the first-order process, reaction rates were found to be independent of [Cr(III)], linearly dependent on [Ag+] and independent of [S2O82–]. The activation enthalpy (ΔH≠) was calculated as 56 ± 5 kJ mol–1, the activation entropy (ΔS≠) as –136 ± 16 J K–1 mol–1 and the activation volume as –5.8 ± 0.7 cm3 mol–1. At low [Cr(III)], the reaction rate was independent of [Cr(III)], linearly dependent on [S2O82–] and non-linearly dependent on [Ag+], reaching a limiting value at high [Ag+]. The activation enthalpy (ΔH≠) was calculated as 61±5kJmol–1, the activation entropy (ΔS≠) as –119±15 J K–1 mol–1 and the activation volume as –1.7±0.1 cm3 mol–1. A mechanism involving the reversible formation of a silver-peroxodisulphate complex that decomposes into oxidizing intermediates is proposed. The empirical observations can be adequately described by this mechanism.Keywords: Chromium(III), peroxodisulphate, oxidation, silver

Syntheses and characterization of vitamin B12-Pt(II) conjugates and their adenosylation in an enzymatic assay

Aiming at the use of vitamin B12 as a drug delivery carrier for cytotoxic agents, we have reacted vitamin B12 with trans-[PtCl(NH3)2(H2O)]+, [PtCl3(NH3)](-) and [PtCl4](2-). These Pt(II) precursors coordinated directly to the Co(III)-bound cyanide, giving the conjugates [(Co)-CN-(trans-PtCl(NH3)2)]+ (5), [(Co)-CN-(trans-PtCl2(NH3))] (6), [(Co)-CN-(cis-PtCl2(NH3))] (7) and [(Co)-CN-(PtCl3)](-) (8) in good yields. Spectroscopic analyses for all compounds and X-ray structure elucidation for 5 and 7 confirmed their authenticity and the presence of the central "Co-CN-Pt" motif. Applicability of these heterodinuclear conjugates depends primarily on serum stability. Whereas 6 and 8 transmetallated rapidly to bovine serum albumin proteins, compounds 5 and 7 were reasonably stable. Around 20% of cyanocobalamin could be detected after 48 h, while the remaining 80% was still the respective vitamin B12 conjugates. Release of the platinum complexes from vitamin B12 is driven by intracellular reduction of Co(III) to Co(II) to Co(I) and subsequent adenosylation by the adenosyltransferase CobA. Despite bearing a rather large metal complex on the beta-axial position, the cobamides in 5 and 7 are recognized by the corrinoid adenosyltransferase enzyme that catalyzes the formation of the organometallic C-Co bond present in adenosylcobalamin after release of the Pt(II) complexes. Thus, vitamin B12 can potentially be used for delivering metal-containing compounds into cells

Maternal and neonatal outcomes after caesarean delivery in the African Surgical Outcomes Study: a 7-day prospective observational cohort study.

BACKGROUND: Maternal and neonatal mortality is high in Africa, but few large, prospective studies have been done to investigate the risk factors associated with these poor maternal and neonatal outcomes. METHODS: A 7-day, international, prospective, observational cohort study was done in patients having caesarean delivery in 183 hospitals across 22 countries in Africa. The inclusion criteria were all consecutive patients (aged ≥18 years) admitted to participating centres having elective and non-elective caesarean delivery during the 7-day study cohort period. To ensure a representative sample, each hospital had to provide data for 90% of the eligible patients during the recruitment week. The primary outcome was in-hospital maternal mortality and complications, which were assessed by local investigators. The study was registered on the South African National Health Research Database, number KZ_2015RP7_22, and on ClinicalTrials.gov, number NCT03044899. FINDINGS: Between February, 2016, and May, 2016, 3792 patients were recruited from hospitals across Africa. 3685 were included in the postoperative complications analysis (107 missing data) and 3684 were included in the maternal mortality analysis (108 missing data). These hospitals had a combined number of specialist surgeons, obstetricians, and anaesthetists totalling 0·7 per 100 000 population (IQR 0·2-2·0). Maternal mortality was 20 (0·5%) of 3684 patients (95% CI 0·3-0·8). Complications occurred in 633 (17·4%) of 3636 mothers (16·2-18·6), which were predominantly severe intraoperative and postoperative bleeding (136 [3·8%] of 3612 mothers). Maternal mortality was independently associated with a preoperative presentation of placenta praevia, placental abruption, ruptured uterus, antepartum haemorrhage (odds ratio 4·47 [95% CI 1·46-13·65]), and perioperative severe obstetric haemorrhage (5·87 [1·99-17·34]) or anaesthesia complications (11·47 (1·20-109·20]). Neonatal mortality was 153 (4·4%) of 3506 infants (95% CI 3·7-5·0). INTERPRETATION: Maternal mortality after caesarean delivery in Africa is 50 times higher than that of high-income countries and is driven by peripartum haemorrhage and anaesthesia complications. Neonatal mortality is double the global average. Early identification and appropriate management of mothers at risk of peripartum haemorrhage might improve maternal and neonatal outcomes in Africa. FUNDING: Medical Research Council of South Africa.Medical Research Council of South Africa